Scientists have investigated a little-known mechanism that fuels cellular senescence: mitochondrial RNA leaking into the cytoplasm. Targeting this mechanism showed promise in a mouse model of fatty liver [1].
The new target
The increasing abundance of senescent cells with age has been linked to numerous diseases and is considered a hallmark of aging. Understanding why cells become senescent, and how we can either save them from this fate or mitigate the consequences, is an important target for geroscience.
It has been known that mitochondria in senescent cells leak mitochondrial DNA into the cytoplasm. The cells’ defense mechanisms often mistake it for viral DNA and trigger response mechanisms that exacerbate the cell’s senescent or pre-senescent state [2]. In a new study coming from Mayo Clinic and published in Nature Communications, a team of scientists focused on a different, much less-studied mechanism: the leakage of mitochondrial RNA.
Mitochondria have their own small circular genomes that encode several proteins essential for the organelle’s function. While the transcription and translation of mtDNA differ from those of nuclear DNA, the basics are the same: DNA is transcribed into RNA and then translated into proteins by ribosomes.
Mitochondrial RNA (mtRNA) can sometimes form double-stranded RNA (mtdsRNA), such as when complementary “sense” and “antisense” mitochondrial transcripts overlap. Because cytosolic dsRNA is a classic viral-like danger signal, its appearance outside mitochondria can trip the cell’s antiviral RNA sensors and set off an inflammatory “fire alarm”, which is similar in spirit to mtDNA leakage but occurs via a different sensing pathway [3].
The mtRNA-senescence connection
The team found that mtdsRNA levels are higher in the cytosol of senescent cells (specifically, fibroblasts), which sets off the RNA sensors RIG-I and MDA5. This happened across multiple senescence triggers (replicative, doxorubicin/etoposide) and cell lines. The levels of those RNA sensors also increase with age in multiple mouse tissues, along with the senescence markers p16 and p21 in addition to SASP factors.
To determine cause and effect, the researchers injected non-senescent fibroblasts with purified mitochondrial RNA, which likely contained and/or generated mtdsRNA. This boosted common SASP factors and RNA sensors, suggesting that the presence of mtRNA in the cytosol is enough to drive the SASP program.
They then did something roughly opposite, depleting mitochondria from already senescent cells. As a result, the cells stopped producing the SASP while still staying senescent. The researchers then added purified mtRNA to the cells to see what its impact would be in the absence of working mitochondria. In these mitochondria-depleted senescent cells, mtRNA add-back partially restored interferon/NF-κB inflammatory transcriptional programs – a key element of SASP regulation – rather than fully restoring SASP secretion.
The researchers then pharmacologically reduced mtRNA production in senescent cells by inhibiting mitochondrial RNA polymerase (POLRMT). This lowered cytosolic mtdsRNA, reduced RNA sensors and several SASP components, but did not lower p16 and p21, which can be interpreted as dampening SASP without reverting senescence. Interestingly, blocking STING to blunt mtDNA sensing reduced SASP more than blocking MAVS to blunt mtRNA sensing, and doing both didn’t help further, suggesting that these pathways overlap, with cGAS-STING likely being the main driver of SASP here.
The researchers suspected that mtRNA escape was driven by pores formed by the proteins BAX and BAK in a subset of mitochondria. Indeed, deleting both BAX and BAK reduced cytosolic mtRNA, lowered RNA sensors, reduced MAVS aggregation, and suppressed SASP components.
In vivo validation
The team validated their findings in a mouse model of metabolic dysfunction-associated steatohepatitis (MASH), a dangerous and increasingly prevalent subtype of fatty liver that is often triggered by obesity. They found increased RNA-sensing/SASP signals in livers of MASH mice and then showed that either hepatocyte-targeted Bax deletion or hepatocyte-targeted MAVS knockdown dampens inflammatory and fibrotic markers.
“Liver scarring and inflammation are hallmarks of MASH,” said Stella Victorelli, Ph.D., who is the lead author of the study. If left untreated, it can progress to liver cancer. This is why it’s so important to understand the mechanisms driving the disease so that we can prevent it or develop more effective treatments.”
“With age, we accumulate ‘zombie’ cells, which can lead to more disease,” added João Passos, Ph.D., senior author of the study. “Our idea is that if we can quiet these cells earlier, we can prevent runaway inflammation and the development of many age-related conditions, including liver disease. Understanding the mechanisms that drive disease allows us to target and delay those processes – potentially benefiting more than one condition.”
Literature
[1] Victorelli, S., Eppard, M., Martini, H., et al. (2025). Mitochondrial RNA cytosolic leakage drives the SASP. Nature Communications, 16, 10992.
[2] Victorelli, S., Salmonowicz, H., Chapman, J., Martini, H., Vizioli, M. G., Riley, J. S., … & Passos, J. F. (2023). Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature, 622(7983), 627-636.
[3] Dhir, A., Dhir, S., Borowski, L. S., Jimenez, L., Teitell, M., Rötig, A., … & Proudfoot, N. J. (2018). Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature, 560(7717), 238-242.
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